Our Progress: Congenital Long QT Syndrome & Drug-Induced Long QT
We have rapidly advanced our portfolio of SGK1 inhibitors to investigate their use as precision therapeutics in various genetic arrhythmias. So far, our progress includes:
Repeated positive in vitro effects on APD90 (a surrogate for QT interval) using our lead SGK1 inhibitor in cardiomyocytes derived from LQTS patient stem cells of all three major Long QT Syndrome Types 1, 2, and 3.
Repeated positive in vitro effects of our lead SGK1 inhibitor in a dofetilide model of drug-induced Long QT using stem cell derived cardiomyocytes.
Completion of all pre-clinical animal toxicology studies necessary for initiation of clinical studies in humans.
Completion of the Phase 1 healthy volunteer study, showing:
LQT-1213 appeared tolerated with good bioavailability and predictable pharmacokinetics.
Mild concentration dependent reductions in QTcF were seen with a single dose of LQT-1213.
Data from the Wave I Part 1 clinical proof of efficacy study: LQT-1213 Rapidly and Meaningfully Reduces QT Interval in Individuals with Prolonged QT Induced by Dofetilide. Read More.
Completion of the Wave I Part 2 study to evaluate the safety, tolerability, and pharmacokinetics of our compound in patients diagnosed with Long QT Syndrome Types 1, 2 & 3. Learn More.
Completion of Long QT Syndrome Types 2 and 3.
Initiation of Long QT Syndrome Type 1 expected to start in 2025.
MyQTWave is a non-interventional and observational study designed to better understand the symptoms and daily challenges faced by individuals living with Long QT Syndrome (LQTS).
Initiation of the non-interventional MyQTWave study for Long QT Syndrome Types 2 and 3 expected to start in 2025.
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Long QT Syndrome (LQTS) is a rare genetic condition that causes an elongation between the Q and T waves during a heartbeat. The lengthening of the interval can lead to unexpected and life-threatening arrhythmias called torsades de pointes. These arrhythmias are generally in response to exercise and stress.
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A prolonged QT interval can be caused by any number of environmental factors including acute and chronic use of certain prescription medications. These therapeutics are prescribed despite the risks of QT prolongation as the risk of a developing an arrhythmia is outweighed by the benefit of the intervention where limited options are available. This risk is obviously more severe in patients with underlying risk factors including cLQTS.
Our Progress: Heart Failure & Atrial Fibrillation
Demonstration of the preventive effect of an SGK1 inhibitor in an animal model of high-fat diet-induced atrial fibrillation.
Demonstration of the treatment and protective effect of SGK1 inhibition in two independent preclinical models of heart failure with preserved ejection fraction (HFpEF). The topline data from these studies were presented at the 2024 American Heart Association (AHA) Scientific Sessions.
Completion of IND/CTA-enabling preclinical studies.
Completion of dosing in the Phase 1 healthy volunteer study.
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Heart Failure is a chronic condition in which the heart's ability to pump blood effectively is impaired, either due to reduced systolic, pumping function (HF with reduced ejection fraction; HFrEF) or with normal systolic function but impaired diastolic filling between beats (HF with preserved ejection fraction; HFpEF). This diminished cardiac performance leads to inadequate blood flow to meet the body's needs, causing symptoms such as fatigue, shortness of breath, reduced ability to exercise, and fluid retention. There are many risks for developing heart failure with some of the most common being coronary artery disease, heart attack (myocardial infarction), high blood pressure, obesity, smoking, excessive alcohol, physical inactivity, family history or genetic disorders.
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Atrial Fibrillation is a type of arrhythmia (irregular heart rhythm) which may present as a rapid, slow, or abnormal heart rate. These arrhythmias reduce the ability of the heart to efficiently to pump blood and may lead to blood clots localized in the heart which can dislodge and increase the risk of stroke, heart failure and other heart-related complications.
What is SGK1 & Selective Inhibition?
Serum and Glucocorticoid Kinase 1 (SGK1) is a protein kinase, which regulates a number of ion currents in human cardiac cells, and works to support cell survival and proliferation in many resistant cancer cells.
Cardiomyocytes - Overactivity of SGK1 has been linked to both cardiac ion channel effects as well as a mediator of fibrotic and inflammatory signaling. SGK1-mediated cardiac ion channel effects result in adverse prolongation of the QT interval in animals and humans leading to both Congenital and Acquired (Drug-Induced) Long QT Syndrome - both of which can lead to the development of lethal arrhythmias. Increased fibrotic and inflammatory signaling due to upregulated SGK1 activity in metabolic disease plays a significant role in the development of atrial fibrillation and heart failure. We are investigating our selective and novel SGK1 inhibitors as therapeutics to modulate ion channel activity in Long QT Syndrome and fibrotic and inflammatory signaling in atrial fibrillation and heart failure.
